The auditory system comprises ascending pathways that transmit information from the ear to higher levels for perception, and descending pathways that can modify how that information is processed at each stage of the ascending pathways. The auditory cortex is the source of massive descending projections that are considered to play a role in a wide range of functions, including selective attention and understanding speech in noisy environments. Progress in understanding these functions is hampered by questions regarding the underlying neural circuitry. The present proposal focuses on one of the largest descending projections, from auditory cortex to the inferior colliculus of the midbrain. One aim is to determine whether these projections make direct synaptic contact with midbrain inhibitory circuits that use the neurotransmitter GABA. A second aim is to determine whether the cortical projections make direct synaptic contact with the large commissural pathway that connects the two sides of the midbrain (and could thus spread the cortical effects). The study will be conducted in guinea pigs, a well-researched model for many aspects of auditory function. The experiments will use multilabeling anatomical techniques, including the use of fluorescent neuronal tracers for labeling specific circuit elements and immunohistochemical techniques for identifying the neurotransmitters associated with those elements. The design includes coordinated studies with both light and electron microscopes to allow for the direct identification of synapses, a necessary step for identifying neuronal circuits. The results will provide an important step in characterizing descending auditory pathways and their relationships to excitatory and inhibitory midbrain circuits. Considerable work has been done on GABAergic circuits and ascending pathways to the midbrain;the current proposal should help to integrate the descending systems into our view of GABAergic mechanisms in the midbrain. This may have important implications for normal function as well as dysfunction (such as presbycusis or tinnitus) associated with aging or injury and for the evolving design and use of cochlear implants and brainstem implants. From a training perspective, the proposed experiments cover a broad range of sensitive anatomical techniques, including a variety of multi-labeling methods and strategies for the effective combination of light and electron microscopy. This anatomical training is designed to complement the applicant's prior, extensive training in neurophysiological techniques. The ability to combine all these approaches will greatly expand the range of research questions that he will be able to address in the future. PUBLIC HEALTH RELEVANCE: Auditory dysfunction due to aging, damage or disease affects many people. Our ability to develop treatments or prosthetics relies in part on identifying the neuronal circuits and the neurotransmitters they use. The present proposal will characterize the connections and neurotransmitters of circuits between the auditory cortex and midbrain that are associated with a wide range of functions.